As the Alzheimer's disease (AD) population is growing rapidly, currently there are no blood tests for AD and no cure treatments. Using the AD mouse model, we have developed a blood test for AD that is analogous to the glucose tolerance test for diabetics. As the glucose tolerance test shows abnormalities only in diabetic patients after the challenge of glucose is given, we have developed a test that measures amyloid- peptide (A) in the blood after the challenge of amylin. Amylin is a peptide that freely passes through the blood brain barrier (BBB) and competes with A to bind to the same receptor and be degraded by the insulin-degrading enzyme (IDE) in the brain. Patients with AD have high levels of A in the brain, so an amylin challenge probably results in a removal of A from the brain to the blood stream where it can be detected. The goal of this revised R21 proposal is to conduct an exploratory study to further support the concept of the amylin challenge test in humans. Instead of amylin, we propose to conduct this challenge test in humans using pramlintide, a synthetic analog of amylin, which already has FDA approval for diabetes and a favorable safety profile. We hypothesize that an increase of A in plasma induced by the pramlintide challenge will provoke an increase of A in the blood among clinically diagnosed AD patients. We expect that the pramlintide challenge has potential to diagnose AD and the prodromal AD in humans through an increase of A in plasma. Aim 1 is to examine whether pramlintide can induce an increase of plasma A in AD vs. those who have normal cognition. Aim 2 is to study whether the result of the pramlintide challenge test is correlated with the AD biomarkers in cerebral spinal fluid (CSF). Aim 3 is to examine the safety of pramlintide in the challenge test.